Influenza infects about 10-20% of the population each year and is a major cause of morbidity and socio- economic burden in US. Routinely prepared vaccines offer ~70% protection against influenza infection, however, a significant variability in the effectiveness of vaccines in individuals is observed. The central hypothesis of this research proposal is that the ability to mount protective responses to vaccine is controlled in part by the host genetic factors. This proposal will utilize high density array (Human Array SNP 6.0, Affymetrix) in order to assess the contribution of immune response (IR) genetic variations that may underlie variable responses to influenza vaccines. Population-based patterns of gene variation will be evaluated to further characterize diversity of the IR genetic loci (Specific Aim 1). Global RNA Expression signature will be determined for 100 Male Caucasian responder and non-responder groups (with respect on measured rise in antibody titer) of an ongoing influenza vaccine trial. Expression quantitative traits (QTT) will be the basis for association with important genetic determinants for vaccine responses (Specific Aim 2). The contribution of the genuinely associated genetic variants will be validated in an independent set of responders and non- responders from approximately ~1500 past clinical participants (Specific Aim2). By inferring the common haplotypes within each group and subsequent data analysis, causative gene variants and haplotypes that confer protective responses to influenza vaccines will be identified. Completion of proposed study will increase our understanding of individual variations in the immune response to vaccines. Knowledge from this study can be further applied to facilitate the design of more effective vaccines with minimized toxicities. The success of the novel study design proposed in this study may eventually serve as a platform to identify the genetic determinants that control other types of immune responses.